The general hypothesis of this grant proposal is that the biological mechanisms responsible for different forms of inherited glaucoma represent different processes that culminate in optic nerve degeneration. Elucidating each mechanism will produce a composite picture of the complex pathophysiology of glaucomatous disease. The objective of this proposal is to characterize genetic defects responsible for inherited glaucoma, and determine the relationship between specific mutations and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will be the basis of new treatment and diagnostic modalities. The specific goal of the previous grant period was to determine the genomic locations of genes responsible for hereditary forms of autosomal dominant glaucoma. During the previous grant cycle, two new loci were identified for autosomal dominant forms of glaucoma: a locus for pigment dispersion syndrome and pigmentary glaucoma mapped to 7q36, and a locus for one form of Rieger syndrome mapping to 13q14 (RIEG2). A locus for juvenile autosomal dominant glaucoma (GLC1A) was confirmed, and two new loci for juvenile glaucoma were suggested by preliminary experiments. During the next grant period the specific aims are to construct detailed physical maps of the pigmentary glaucoma locus on 7q36, and the RIEG2 critical region, to identify candidate genes for these conditions, and to ascertain new pedigrees affected by forms of glaucoma inherited as Mendelian traits. Physical mapping will utilize BAC clones, STS content mapping and critical recombinant analysis. Candidate genes identified as ESTs, cDNAs or previously cloned genes will be located on the physical maps and will be screened for mutations. Newly ascertained pedigrees will be used for further studies to confirm existing loci, to identify new loci and to correlate specific genetic defects with important aspects of the clinical phenotype.